title: Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats.
abstract: BACKGROUND
  Multiple mechanisms contribute to the liver fibrosis following cholestasis. Recent research has focused on the role of transforming growth factor β-1 (TGF-β1) in the progression of fibrosis. The aim of our study is to examine the role of epigenetic chromatin marks, such as histone H3 lysine methylation (H3Kme), in bile duct ligation (BDL)-induced TGF-β1 gene expression in rat liver.
  
  
  METHODS
  Time course of methylated-histone H3 and SET7/9 recruitment were determined by chromatin immunoprecipitation in livers from BDL rats on days 1, 4, 9 and 14. Levels of TGF-β1 and SET7/9 were determined by western blots. The effect of SET7/9 knockdown on BDL-induced expression of TGF-β1, serum enzymes and liver collagen content was studied in vivo.
  
  
  RESULTS
  Results showed that BDL increased the expression of the TGF β-1. Increased levels of active chromatin marks (H3K4me1, H3K4me2, and H3K4me3) and decreased levels of repressive marks (H3K9me2 and H3K9me3) in TGF-β1 promoter accompanied the changes in expression of the TGF β-1. BDL also increased expression of the H3K4 methyltransferase SET7/9 and recruitment to the promoter. SET7/9 gene knockdown with siRNAs significantly attenuated BDL-induced TGF-β1 gene expression, serum enzymes and liver collagen content.
  
  
  CONCLUSIONS
  Taken together, these results show the functional role of epigenetic chromatin histone H3Kme in BDL-induced TGF-β1 expression. Pharmacologic and other therapies that reverse these modifications could have potential hepatoprotective effects for BDL-induced cirrhosis.
authors.affiliation: Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung, 833, Taiwan.
authors.forename: Shyr-Ming
authors.initials: SM
authors.lastname: Sheen-Chen
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Lin
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Chen
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Yang
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lee
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Huang
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D003094:Collagen; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008297:Male; D008745:Methylation; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D003094:Collagen; D011495:Histone-Lysine N-Methyltransferase